The development of a vaccine against human malignancies has been a long-sought goal which has yet to be achieved. Many of the efforts toward this end have been frustrated by the lack of identification of a tumor-specific antigen which would allow tumor cells to be distinguished from normal cells. Conceptually, such an antigen could be used as a vaccine to induce the host's immune system to reject cells bearing that antigen.
Immunoglobulin (Ig) molecules are composed of heavy and light chains, which possess highly specific variable regions at their amino termini. The variable regions of heavy and light chains combine to form the unique antigen-recognition site of the Ig protein. These variable regions contain determinants (molecule shapes) that can themselves be recognized as antigens, or idiotypes (Id).
B-cell malignancies are composed of clonal proliferations of cells synthesizing a single antibody molecule with unique variable regions in the heavy and light chains. B-cell lymphomas and myelomas are neoplasms of mature lymphocytes which generally express and/or secrete synthesized Ig. The idiotypic determinants of the surface Ig of a B-cell lymphoma or myeloma can thus serve as a tumor-specific marker for the malignant clone.
Studies in experimental animals, as well as in man, have demonstrated the utility of the Ig idiotype as a tumor-specific antigen for the study of the biology of B-cell lymphoma in vitro and as a target for passive immunotherapy in vivo (1-3). Furthermore, active immunization against idiotypic determinants on malignant B-cells has been demonstrated to produce resistance to tumor growth in a number of syngeneic experimental tumor models, as well as specific anti-tumor therapy against established tumors (4-). Furthermore, preclinical studies in subhuman primates demonstrated that optimal immunization with human lymphoma-derived Id required conjugation of the protein to an immunogenic protein carrier (keyhole limpet hemocyanin (KLH)) and emulsification in an adjuvant (15). These results, taken together, provided the rationale for testing autologous tumor-derived idiotypic surface Ig (Id) as a therapeutic "vaccine" against human B-cell malignancies.
The mainstay of therapy for advanced stage myeloma patients with symptoms and signs of progressive disease remains systemic chemotherapy, particularly with alkylating agents and steroids. There is still some controversy regarding the superior efficacy of multiagent intensive chemotherapy regimens, such as the M2 or alternating combination chemotherapy regimens described by the Southwest Oncology Group and Medical Research Council, but most randomized trial results demonstrate only a modest incremental advantage in long-term overall survival compared with standard melphalan and prednisone, with no significant numbers of long-term disease-free survivors (16-23). Thus, although partial remissions of up to 60% are obtained with a variety of regimens, the median survival of about 30 months has remained constant for the last 30 years.
A more aggressive approach with intensive high dose chemoradiotherapy with either autologous or allogeneic bone marrow transplantation (BMT) is currently being explored by several groups of investigators. These protocols have improved initial response rates, although it remains to be seen whether these remissions are maintained with longer follow-up periods (24-28). Regardless of the initial responsiveness rates, the vast majority (&gt;90%) of patients currently treated by these methods experience an eventual relapse of the tumor.
Many groups have described monoclonal B-cell populations in the peripheral blood as well as in the bone marrow of patients with myeloma, and these cells bear the myeloma protein idiotype on their surface as evidence of the clonal identity with the malignant plasma cells (29-37). As the removal of malignant plasma cells by chemotherapy does not appear to deplete the malignant stem cell (38), eradication of these precursor B-cells may ultimately be necessary for successful treatment of this disease.
The goal of the specific strategy described herein was to attempt to transfer tumor antigen-specific immunity induced in a bone marrow donor to a sibling BMT recipient with myeloma, as a means to enhance the therapeutic efficacy of allogeneic BMT. The transfer of induced antigen-specific humoral immunity to viral and other pathogens from immune donors has been explored in BMT patients as a potential therapeutic approach to the problem of increased host susceptibility to infection following the BMT procedure (39-42). A recent report also suggested the possible transfer of Varicella Zoster Virus specific cellular immunity from immune marrow donors to BMT recipients (43). This report, however, was inconclusive as to the origin of the cellular immunity response due to the immunization of both the donor and the recipient. Moreover, the literature reports that transfer of specific cellular immunity cannot be achieved in the context of transplantation (40).
Until this invention only a small percentage (&lt;10%) of investigators had succeeded in eradicating a myeloma through BMT. This percentage is even smaller in the case of patients in the advanced stages of myeloma. The literature does not show that an immune response, and specifically a cellular immune response to a tumor specific antigen, could be transferred exclusively from an immunized donor in a BMT. Thus, donor immunization with myeloma Id represents a very important strategy for enhancing the specific anti-tumor effect of allogeneic marrow grafts.